Focal segmental glomerulosclerosis (FSGS) is a histological lesion with many causes, including inherited genetic defects, with significant proteinuria being the predominant clinical finding at ...presentation. Mutations in COL4A3 and COL4A4 are known to cause Alport syndrome (AS), thin basement membrane nephropathy, and to result in pathognomonic glomerular basement membrane (GBM) findings. Secondary FSGS is known to develop in classic AS at later stages of the disease. Here, we present seven families with rare or novel variants in COL4A3 or COL4A4 (six with single and one with two heterozygous variants) from a cohort of 70 families with a diagnosis of hereditary FSGS. The predominant clinical finding at diagnosis was proteinuria associated with hematuria. In all seven families, there were individuals with nephrotic-range proteinuria with histologic features of FSGS by light microscopy. In one family, electron microscopy showed thin GBM, but four other families had variable findings inconsistent with classical Alport nephritis. There was no recurrence of disease after kidney transplantation. Families with COL4A3 and COL4A4 variants that segregated with disease represent 10% of our cohort. Thus, COL4A3 and COL4A4 variants should be considered in the interpretation of next-generation sequencing data from such patients. Furthermore, this study illustrates the power of molecular genetic diagnostics in the clarification of renal phenotypes.
Acute kidney injury (AKI) and chronic kidney disease (CKD) are common syndromes associated with significant morbidity, mortality and cost. The extent to which repeated AKI episodes may cumulatively ...affect the rate of progression of all-cause CKD has not previously been investigated. In this study, we explored the hypothesis that repeated episodes of AKI increase the rate of renal functional deterioration loss in patients recruited to a large, all-cause CKD cohort.
Patients from the Salford Kidney Study (SKS) were considered. Application of KDIGO criteria to all available laboratory measurements of renal function identified episodes of AKI. A competing risks model was specified for four survival events: Stage 1 AKI; stage 2 or 3 AKI; dialysis initiation or transplant before AKI event; death before AKI event. The model was adjusted for patient age, gender, smoking status, alcohol intake, diabetic status, cardiovascular co-morbidities, and primary renal disease. Analyses were performed for patients' first, second, and third or more AKI episodes.
A total of 48,338 creatinine measurements were available for 2287 patients (median 13 measures per patient IQR 6-26). There was a median age of 66.8years, median eGFR of 28.4 and 31.6% had type 1 or 2 diabetes. Six hundred and forty three (28.1%) patients suffered one or more AKI events; 1000 AKI events (58% AKI 1) in total were observed over a median follow-up of 2.6 years IQR 1.1-3.2. In patients who suffered an AKI, a second AKI was more likely to be a stage 2 or 3 AKI than stage 1 HR 2.04, p 0.01. AKI events were associated with progression to RRT, with multiple episodes of AKI progressively increasing likelihood of progression to RRT HR 14.4 after 1 episode of AKI, HR 28.4 after 2 episodes of AKI. However, suffering one or more AKI events was not associated with an increased risk of mortality.
AKI events are associated with more rapid CKD deterioration as hypothesised, and also with a greater severity of subsequent AKI. However, our study did not find an association of AKI with increased mortality risk in this CKD cohort.
Patients with atherosclerotic renovascular disease (ARVD) and high-risk clinical presentations have largely been excluded from randomized controlled trials comparing renal revascularization and ...optimal medical therapy. Here, we explore the effect of revascularization on death, progression to end-stage kidney disease (ESKD) and cardiovascular events (CVE) in a highly selected cohort of patients with ARVD.
All patients with a radiological diagnosis of ARVD referred to our tertiary centre have been recruited into a single-centre cohort study between 1986 and 2014. Patients with ≥70% unilateral or bilateral ARVD together with one or more of the following putative high-risk presentations were designated 'high-risk': flash pulmonary oedema (FPE), severe hypertension, rapidly deteriorating renal function. The effect of revascularization on clinical outcomes in high-risk patients, patients with bilateral severe ARVD and those with <1 g proteinuria at baseline was compared with 'control' patients who had the same degree of renal artery stenosis (RAS) but did not exhibit these features.
Median follow-up was 58.4 months interquartile range (IQR) 25.4-97.3. Revascularization was associated with a reduced risk of progression to ESKD, CVE and all combined events in patients with rapidly deteriorating renal function ESKD: hazard ratio (HR) 0.47 (95% confidence interval, CI, 0.25-0.85), P = 0.01; CVE: HR 0.51 (95% CI 0.29-0.91), P = 0.02; Any: HR 0.51 (95% CI 0.29-0.90), P = 0.02. High-risk patients with bilateral ≥70% RAS and those with <1 g/day baseline proteinuria also had significantly better renal and cardiovascular outcomes post-revascularization when compared with controls.
Our results indicate that revascularization may be of benefit in patients with anatomically significant RAS who present with rapidly deteriorating renal function, especially in the presence of severe bilateral ARVD or <1 g/day proteinuria.
Abstract
Patients with chronic kidney disease are at increased risk of cardiovascular disease and this often manifests clinically like heart failure. Conversely, patients with heart failure ...frequently have reduced kidney function. The links between the kidneys and cardiovascular system are being elucidated, with blood pressure being a key risk factor. Patients with heart failure have benefitted from many trials which have now established a strong evidence based on which to base management. However, patients with advanced kidney disease have often been excluded from these trials. Nevertheless, there is little evidence that the benefits of such treatments are modified by the presence or absence of kidney disease, but more direct evidence among patients with advanced kidney disease is required. Neprilysin inhibition is the most recent treatment to be shown to improve outcomes among patients with heart failure. The UK HARP-III trial assessed whether neprilysin inhibition improved kidney function in the short- to medium-term and its effects on cardiovascular biomarkers. Although no effect (compared to irbesartan control) was found on kidney function, allocation to neprilysin inhibition (sacubitril/valsartan) did reduce cardiac biomarkers more than irbesartan, suggesting that this treatment might improve cardiovascular outcomes in this population. Larger clinical outcomes trials are needed to test this hypothesis.
Sudden cardiac death (SCD) is the leading cause of death in hemodialysis patients, accounting for death in up to one-quarter of this population. Unlike in the general population, coronary artery ...disease and heart failure often are not the underlying pathologic processes for SCD; accordingly, current risk stratification tools are inadequate when assessing these patients. Factors assuming greater importance in hemodialysis patients may include left ventricular hypertrophy, electrolyte shift, and vascular calcification. Knowledge regarding SCD in hemodialysis patients is insufficient, in part reflecting the lack of an agreed-on definition of SCD in this population, although epidemiologic studies suggest the most common times for SCD to occur are toward the end of the long 72-hour weekend interval between dialysis sessions and in the 12 hours immediately after hemodialysis. Accordingly, it is hypothesized that the dialysis procedure itself may have important implications for SCD. Supporting this is recognition that hemodialysis is associated with both ventricular arrhythmias and dynamic electrocardiographic changes. Importantly, echocardiography and electrocardiography may show changes that are modifiable by alterations to dialysis prescription. The most effective preventative strategy in the general population, implanted cardioverter-defibrillator devices, are less effective in the presence of chronic kidney disease and have not been studied adequately in dialysis patients. Last, many dialysis patients experience SCD despite not fulfilling current criteria for implantation, making appropriate allocation of defibrillators uncertain.
To assess the frequency of chronic kidney disease (CKD), define the associated demographics, and evaluate its association with use of evidence-based drug therapy in a contemporary global study of ...patients with stable coronary artery disease.
22,272 patients from the ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease (CLARIFY) were included. Baseline estimated glomerular filtration rate (eGFR) was calculated (CKD-Epidemiology Collaboration formula) and patients categorised according to CKD stage: >89, 60-89, 45-59 and <45 mL/min/1.73 m2.
Mean (SD) age was 63.9±10.4 years, 77.3% were male, 61.8% had a history of myocardial infarction, 71.9% hypertension, 30.4% diabetes and 75.4% dyslipidaemia. Chronic kidney disease (eGFR<60 mL/min/1.73 m2) was seen in 22.1% of the cohort (6.9% with eGFR<45 mL/min/1.73 m2); lower eGFR was associated with increasing age, female sex, cardiovascular risk factors, overt vascular disease, other comorbidities and higher systolic but lower diastolic blood pressure. High use of secondary prevention was seen across all CKD stages (overall 93.4% lipid-lowering drugs, 95.3% antiplatelets, 75.9% beta-blockers). The proportion of patients taking statins was lower in patients with CKD. Antiplatelet use was significantly lower in patients with CKD whereas oral anticoagulant use was higher. Angiotensin-converting enzyme inhibitor use was lower (52.0% overall) and inversely related to declining eGFR, whereas angiotensin-receptor blockers were more frequently prescribed in patients with reduced eGFR.
Chronic kidney disease is common in patients with stable coronary artery disease and is associated with comorbidities. Whilst use of individual evidence-based medications for secondary prevention was high across all CKD categories, there remains an opportunity to improve the proportion who take all three classes of preventive therapies. Angiotensin-converting enzyme inhibitors were used less frequently in lower eGRF categories. Surprisingly the reverse was seen for angiotensin-receptor blockers. Further evaluation is required to fully understand these associations. The CLARIFY (ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) Registry is registered in the ISRCTN registry of clinical trials with the number ISRCTN43070564. http://www.controlled-trials.com/ISRCTN43070564.
Non-alcoholic fatty liver disease (NAFLD) is recognised to be a strong risk factor for causing cardiovascular disease (CVD) and chronic kidney disease (CKD), independent of the presence of diabetes ...mellitus. The association of NAFLD with outcomes in patients with diabetic kidney disease (DKD) has been variably reported. This study aimed to investigate the association of NAFLD with cardiovascular, renal outcomes and mortality in patients with advanced DKD (CKD 3-5, not on dialysis).
This observational study was carried out on 192 patients with DKD within a cohort of 2,974 non-dialysis CKD patients, who had an ultrasound (US) of their liver done between January 2000 and end of December 2014. From these 192 patients, 149 patients (NAFLD 48 and normal US 101) were included for comparative analysis, as they had complete datasets. Patient demographics, comorbidities and blood results were collected at study baseline. Follow-up data on non-fatal cardiovascular events (NFCVE), mortality and serial estimated glomerular filtration rate (eGFR) was gathered until study end point. Cox-regression analysis was used to study the association of NAFLD with NFCVE and mortality, and linear regression analysis was used for the estimation of renal progression.
Median follow-up time was 69 months, similar in both groups (p = 0.09). Median eGFR was 31.6 mL/min/1.73 m2, with a median urine protein creatinine ratio of 46 g/mol. A total of 20 (41.7%) NFCVE were recorded in the NAFLD group compared to 14 (13.9%) in the normal US group. Multivariable Cox-regression analysis showed NAFLD as an independent risk factor (hazard ratio 2.95; 95% CI 1.31-6.60; p = 0.01) for NFCVE even after including all cardiovascular risks parameters that were significant in the univariable model. There was no significant difference in survival between the 2 groups over the follow-up period (log-rank test, p = 0.76). The overall rate of decline in eGFR was 3.46 mL/min/1.73 m2/year and this was not observed to be different between the groups (p = 0.65).
In our cohort of patients with advanced DKD, NAFLD showed a strong independent association with cardiovascular outcomes. Further prospective studies are warranted to strengthen these associations and plan a strategy for screening NAFLD in this high-risk group.
There is emerging evidence that the 4-variable Kidney Failure Risk Equation (KFRE) can be used for risk prediction of graft failure in transplant recipients. However, geographical validation of the ...4-variable KFRE in transplant patients is lacking, as is whether the more extensive 8-variable KFRE improves predictive accuracy. This study aimed to validate the 4- and 8-variable KFRE predictions of the 5-year death-censored risk of graft failure in patients in the United Kingdom.
A retrospective cohort study involved 415 transplant recipients who had their first renal transplant between 2003 and 2015 and were under follow-up at Salford Royal NHS Foundation Trust. The KFRE risk scores were calculated on variables taken 1-year post-transplant. The area under the receiver operating characteristic curves (AUC) and calibration plots were evaluated to determine discrimination and calibration of the 4- and 8-variable KFREs in the whole cohort as well as in a subgroup analysis of living and deceased donor recipients and in patients with an eGFR< 45 ml/min/1.73m
.
There were 16 graft failure events (4%) in the whole cohort. The 4- and 8-variable KFREs showed good discrimination with AUC of 0.743 (95% confidence interval CI 0.610-0.876) and 0.751 (95% CI 0.629-0.872) respectively. In patients with an eGFR< 45 ml/min/1.73m
, the 8-variable KFRE had good discrimination with an AUC of 0.785 (95% CI 0.558-0.982) but the 4-variable provided excellent discrimination in this group with an AUC of 0.817 (0.646-0.988). Calibration plots however showed poor calibration with risk scores tending to underestimate risk of graft failure in low-risk patients and overestimate risk in high-risk patients, which was seen in the primary and subgroup analyses.
Despite adequate discrimination, the 4- and 8-variable KFREs are imprecise in predicting graft failure in transplant recipients using data 1-year post-transplant. Larger, international studies involving diverse patient populations should be considered to corroborate these findings.
Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective ...longitudinal study examined whether phosphate level was associated with death in a referred population.
Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets.
Mean (SD) eGFR was 32 (15) ml/min per 1.73 m(2), age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality.
In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival.
Background and aims
Calciphylaxis is a rare condition associated with very high mortality in patients with end-stage kidney disease. Data from country-based registries have been an invaluable ...resource for a better understanding of the natural history and management for this condition. This study aimed to investigate the current management strategies and outcomes of patients enrolled in the United Kingdom Calciphylaxis study (UKCS).
Methods
The study was conducted on 89 patients registered in the UKCS since 2012. The initial analysis included a description of the baseline characteristics, management strategies and outcomes on follow-up until May 2020. Further analysis included a comparison of the mortality outcome of the UKCS patients who were receiving haemodialysis with a propensity score matched cohort of haemodialysis patients from the Chronic Renal Insufficiency Standards Implementation Study- Haemodialysis (CRISIS-HD).
Results
Median age of the cohort was 59 years, with a predominance of females (61%) and Caucasian (95%) ethnicity. About 54% of the patients were diabetic and 70% were receiving haemodialysis at study entry. The skin lesions were mostly distributed in the lower extremities (48%). Sodium thiosulphate and calcimimetic were the most widely used management strategies. The mortality rate was 72 deaths per hundred patient-years (50 deaths observed in 69.5 patient years). Complete wound healing was noted in 17% and bacteraemia was reported in 26% of patients. In a comparative analysis of the matched haemodialysis patients, the presence of calciphylaxis in 62 patients showed a strong association with all-cause mortality (HR 6.96; p < 0.001), with annual mortality 67% versus 10.2% in haemodialysis patients without calciphylaxis.
Conclusions
This UK wide study strengthens the evidence that calciphylaxis is a strong and independent risk factor associated with all-cause mortality; no significant benefit was shown with any individual treatment modality. Until further evidence becomes available, a multifaceted approach would be the appropriate treatment strategy in the management of this extremely serious condition.
Graphic abstract
PDF
